Physiological and pharmacological modulation of cardiac contractile proteins

Abstract

Pagani, E.D., and P.J. Silver: Physiological and pharmacological modulation of cardiac contractile proteins. Drug Dev. Res. 18:279-293, 1989.The contractile-relaxation cycle of cardiac muscle is dependent upon the coordination of a variety of membrane and cytosolic events. The functional activities of the structures responsible for these events can be altered by endogenous modulators, on both a beatto-beat or a long-term basis, in order to optimize cardiac performance and meet the circulatory and nutritional needs of the body. This review focuses on the force-generating structures, or myofibrils, of cardiac muscle, its activation by intracellular calcium, and the ways that activation of the myofibrillar proteins can be modulated by physiological and pharmacological mechanisms. Activation of the myofibrillar proteins is regulated by the troponin-tropomyosin system of the actin (thin) filament; when troponin C binds calcium, sites along the thin filament are made available for myosin (thick) filament interaction. There are a number of physiological mechanisms that influence the affinity of troponin C for calcium, three of which include troponin I phosphorylation, intracellular pH, and muscle length. The relative affinity of troponin C for calcium decreases in parallel with a reduction in muscle length and intracellular pH and in parallel with an increase in troponin I phosphorylation. The type of myosin (isozyme) present in cardiac tissue also regulates myofibrillar activity. Ventricular muscle can contain up to three isozymes of myosin ( V l , V2, and V3). Myofibrils containing only the V1 myosin isozyme can have an ATPase activity two to threefold higher than myofibrils containing only the V3 myosin isozyme. The type of myosin isozyme present in cardiac tissue is determined by a variety of factors: thyrotoxicosis and strenuous exercise tend to increase the relative amount of the V1 isozyme, whereas insulin 280Pagani and Silver and thyroxine insufficiency as well as aortic and pulmonary stenosis tend to decrease the relative amount of the V1 isozyme. Besides these physiological mechanisms, there are a variety of pharmacological agents that have been shown to alter the calcium activation (sensitize or desensitize) and/or maximal activity (potentiate or attenuate) of the cardiac contractile proteins. Some cardiotonic agents which increase the calcium sensitivity of the contractile proteins are AR-L 11 5BS (Sulmazole), pimobendan,. However, some of these compounds are not selective and have ancillary activities, such as inhibiting cyclic nucleotide phosphodiesterase, so a single direct link to cardiotonic activity cannot be made. In addition to this class of agents, some calmodulin antagonists also can modulate cardiac contractile protein activity via modulation of calcium binding to troponin C. Some of the calcium-binding protein modulators, such as calmidazolium, trifluoperazine, perhexiline, and bepridil are several times more potent in increasing myofibrillar ATPase activity than either AR-L 1 15BS or ...

Cardiac Troponins in Dogs and Cats

“…Thick myosin filaments cross‐link at the sarcomere center from where they interdigitate with the actin filaments. A myosin filament contains a series of myosin molecules, each with a helical tail and two globular heads . During muscle contraction the many globular heads of a myosin filament repetitively interact with actin in a cross‐bridge cycle, thereby pulling the thin filament along the thick filament to shorten the sarcomere.…”

“…During muscle contraction the many globular heads of a myosin filament repetitively interact with actin in a cross‐bridge cycle, thereby pulling the thin filament along the thick filament to shorten the sarcomere. During muscle relaxation the sites of actin and myosin interaction are sterically blocked by the protein tropomyosin residing in the actin helical groove and a ternary cardiac troponin protein complex located at regular intervals along the actin filament . Troponin consists of 3 subunits which together function as the molecular switch of cardiomyocyte contraction.…”

“…A myosin filament contains a series of myosin molecules, each with a helical tail and two globular heads. [2][3][4] During muscle contraction the many globular heads of a myosin filament repetitively interact with actin in a cross-bridge cycle, thereby pulling the thin filament along the thick filament to shorten the sarcomere. During muscle relaxation the sites of actin and myosin interaction are sterically blocked by the protein tropomyosin residing in the actin helical groove and a ternary cardiac troponin protein complex located at regular intervals along the actin filament.…”

Effect of calcium binding protein modulators on myofibrillar MgATPase activity and cGMP‐inhibitable phosphodiesterase activity from human cardiac muscle

“…Through normal physiological mechanisms, the relation between calcium and myofibrillar activation appears to be regulated on both a beat-to-beat and long-term basis; for example, by changes in intracellular pH [Blanchard and Solaro, 1984;Solaro et al, 19891, through changes in the extent of phosphorylation of another protein subunit of the troponin complex, troponin I [Kay and England, 1976;Holroyde et al, 19791, or through alterations in the expression of isoforms of myofibrillar regulatory proteins [Tobacman and Lee, 1987;McAuliffe et al, 19901. The relation between Ca2+ and myofibrillar activation can also be altered pharmacologically by agents that have been proposed to affect either Ca" binding to troponin C [Solaro and Riiegg, 1982;Pagani and Silver 1989;Smith and England, 1990;Ovaska and Taskinen, 19911 or the transduction of Ca2+ binding to troponin C to myofibrillar activation [ Kurebayashi and Ogawa, 19881. Because the chemical structure and proposed mechanism of action of these types of agents can be quite different, they have been referred to generically as calcium binding protein modulators [Silver and Monteforte, 19881. A number of these types of agents have been evaluated for their effects on myofibrils isolated from nonfailing hearts of dogs, pigs, ferrets, hamsters, and guinea pigs [ Solaro and Riiegg, 1982;Solaro, et al, 1986;Freund et al, 1987;Kitada et al, 1987a;Silver and Monteforte, 1988;Hajjar and Gwathmey, 19911.…”

“…However, based on clinical and preclinical studies of myocardial ischemia and failure, a number of theoretical reasons against developing these types of drugs for the treatment of systolic heart failure have been expressed [Katz, 1986;Packer and Leigh, 19871. A host of undesirable effects have been indirectly or directly attributed to uncontrolled and excessive elevations in cytosolic calcium in cardiac muscle cells induced by, for example, ischemia [for review see Reimer and Jennings, 19921 or ouabain [Pilati and Paradise, 19841 and catecholamine [Fleckenstein et al, 19751 toxicity. Enhancing cardiac contractility without increasing intracellular calcium, however, may have benefits for the treatment of certain types of heart failure [Colucci et al, 1986a;Colucci et al, 198617;Riiegg, 1986;Pagani and Alousi, 1987;Pagani and Silver 1989;Lee and Allen, 19901. Through normal physiological mechanisms, the relation between calcium and myofibrillar activation appears to be regulated on both a beat-to-beat and long-term basis; for example, by changes in intracellular pH [Blanchard and Solaro, 1984;Solaro et al, 19891, through changes in the extent of phosphorylation of another protein subunit of the troponin complex, troponin I [Kay and England, 1976;Holroyde et al, 19791, or through alterations in the expression of isoforms of myofibrillar regulatory proteins [Tobacman and Lee, 1987;McAuliffe et al, 19901.…”